The present invention relates to new piperidyl- or piperazinyl-substituted dihydro-2H-1-benzopyran derivatives as (R)-enantiomers, (S)-enantiomers or racemates in the form of free base or pharmaceutically acceptable salts or solvates thereof, a process for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy.
An object of the invention is to provide compounds for therapeutic use, especially compounds having a selective effect at a subgroup of 5-hydroxytryptamine receptors, designated the h5-HT1B-receptor (previously called the 5-HT1Dxcex2-receptor) in mammals including man.
It is also an object of the invention to provide compounds with a therapeutic effect after oral administration.
Various central nervous system disorders such as depression, anxiety, etc. appear to involve the disturbance of the neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine (5-HT), the latter also known as serotonin. The drugs most frequently used in the treatment of depression are believed to act by improving the neurotransmission of either or both of these physiological agonists. It appears that the enhancement of 5-HT neurotransmission primarily affects the depressed mood and anxiety, whereas the enhancement of noradrenaline neurotransmission affects the retardation symptoms occurring in depressed patients. The invention concerns compounds which have an effect on 5-HT neurotransmission.
Serotonin, or 5-HT, activity is believed to be involved in many different types of psychiatric disorders. For instance it is believed that an increase in 5-HT activity is associated with anxiety, while a decrease in 5-HT release has been associated with depression. Serotonin has in addition been implicated in such diverse conditions as eating disorders, gastrointestinal disorders, cardiovascular regulation disorders and sexual disturbances.
The 5-HT Receptors
The various effects of 5-HT may be related to the fact that serotoninergic neurons stimulate the secretion of several hormones, e.g. cortisol, prolactin, xcex2-endorphin, vasopressin and others. The secretion of each of these other hormones appears to be regulated on a specific basis by several different 5-HT (serotonin) receptor subtypes. With the aid of molecular biology techniques, to date these receptors have been classified as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 with the 5-HT1 receptor further divided into the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F subtypes. Each receptor subtype is involved in a different serotonin function and has different properties.
Regulation of the 5-HT Transmission
The release of 5-HT is feedback-regulated by two different subtypes of 5-HT receptors. Inhibitory 5-HT1A autoreceptors are located on the cell bodies in the raphxc3xa9 nuclei which upon stimulation by 5-HT decrease the impulse propagation in the 5-HT neurons and thereby reduce the 5-HT released at the nerve terminals. Another subtype of inhibitory 5-HT receptors is located on the 5-HT nerve terminals, the h5-HT1B receptors (in rodents the R5-HT1B receptors) which regulate the synaptic concentration of 5-HT by controlling the amount of 5-HT that is released. An antagonist of these terminal autoreceptors thus increases the amount of 5-HT released by nerve impulses which has been shown in both in vitro and in vivo experiments.
The use of an antagonist of the terminal h5-HT1B autoreceptor will accordingly increase the synaptic 5-HT concentration and enhance the transmission in the 5-HT system. It would thus produce an antidepressant effect making it useful as a medication for depression.
Other localizations of h5-HT1B receptor subtype also exist. A large part of these postsynaptic receptors appear to be located on nerve terminals of other neuronal systems (so called heteroreceptors). Since the h5-HT1B receptor mediates inhibitory responses an antagonist of this receptor subtype might also increase the release of other neurotransmitters than 5-HT.
Compounds having h5-HT1B activity may according to well known and recognised pharmacological tests be divided into full agonists, partial agonists and antagonists.
The object of the present invention is to provide compounds having a selective effect at the h5-HT1B receptor, preferably antagonistic properties, as well as having a good bioavailability. The effect on the other receptors chosen from, for example, the 5-HT1A, 5-HT2A, D1, D2A, D3, xcex11 and xcex12 receptor has been investigated.
Accordingly, the present invention provides compounds of the formula I 
wherein
X is N or CH;
Y is NR2CH2, CH2xe2x80x94NR2, NR2xe2x80x94CO, COxe2x80x94NR2, NR2SO2 or NR2CONR2 
wherein R2 is H or C1-C6 alkyl;
R1 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R3 is C1-C6 alkyl, C3-C6 cycloalkyl or (CH2)n-aryl,
wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R4 and/or R5;
wherein R4 is H, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, CN, CF3, OH, C1-C6 alkoxy, NR6R7, OCF3, SO3CH3, SO3CF3, SO2NR6R7, phenyl phenyl-C1-C6 alkyl, phenoxy, C1-C6 alkylphenyl, an optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2 wherein the substituent(s) is(are) selected from C1-C6 alkyl, C3-C6 cycloalkyl, phenyl-C1-C6 alkyl, (CH2)mOR9 wherein m is 2-6 and R9 is H, C1-C6 alkyl, C3-C6 cycloalkyl or phenyl-C1-C6 alkyl, and COR8, an optionally substituted heteroaromatic ring containing one or two heteroatoms selected from N, O and S wherein the substituent(s) is(are) selected from C1-C6 alkyl, C3-C6 cycloalkyl and phenyl-C1-C6 alkyl, or COR8;
wherein R6 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R7 is H, C1-C6 alkyl or C3-C6 cycloalkyl; and
R8 is C1-C6 alkyl, C3-C6 cycloalkyl CF3, NR6R7, phenyl, a heteroaromatic ring containing one or two heteroatoms selected from N, O and S or a heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2;
R5 is H, OH, CF3, OCF3, halogen, C1-C6 alkyl or C1-C6 alkoxy;
and n is 0-4;
as (R)-enantiomers, (S)-enantiomers or a racemate in the form of a free base or a pharmaceutically acceptable salt or solvate thereof which possess a high selective effect at the h5-HT1B receptor and also show sufficient bioavailability after oral administration.
In the present context C1-C6 alkyl may be straight or branched. C1-C6 alkyl may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl
In the present context C1-C6 alkoxy may be straight or branched. C1-C6 alkoxy may be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy, neo-pentyloxy, n-hexyloxy or i-hexyloxy.
In the present context C3-C6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclohexyl.
In the present context halogen may be fluoro, chloro, bromo or iodo.
In the present context the heteroaromatic ring containing one or two heteroatoms selected from N, O and S preferably is a 5- or 6-membered heteroaromatic ring and may be furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyl. The heteroaromatic ring can be either substituted or unsubstituted.
In the present context the heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2 may optionally contain a carbonyl function and is preferably a 5-, 6- or 7-membered heterocyclic ring and may be imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, preferably piperidino, 1-piperazinyl, morpholino, thiomorpholino and 4-piperidon-1-yl.
A preferred embodiment of the invention relates to compounds of formula I wherein Y is NHCO or CONH i.e. amides. Of these compounds, the compounds wherein R3 is unsubstituted phenyl, or mono- or di-substituted phenyl, and especially ortho-, meta- or para-substituted phenyl, and particularly these wherein the substituent R4 is phenyl, phenyl-C1-C6 alkyl, cyclohexyl, piperidino, 1-piperazinyl, morpholino, CF3, 4-piperidon-1-yl, n-butoxy or COR8 wherein R8 is phenyl, cyclohexyl, 4-piperidon-1-yl, 1-piperazinyl, morpholino, CF3, piperidino or NR6R7, are preferred.
Examples of Combinations of Substituents Are
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidino, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is hydroxyethyl-piperazinyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H;
X is N, Y is CONR2; R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidino, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is hydroxyethyl-piperazinyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperidino, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is benzyloxyethyl-piperazinyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)-phenyl;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidino, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is morpholino, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholino, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is benzyloxyethyl-piperazinyl, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is morpholino;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholino, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is COR8, R8 is NR6R7, R6R7CH3, C2H5 or C3H7;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholino, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is morpholino;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is morpholino, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperazinyl, R5 is H;
X is CH, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is piperidino, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl, R4 is phenyl, phenylmethyl or phenylethyl, R5 is H;
X is CH, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is piperidino, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is (CH2)2-phenyl, R4 is morpholino, R5 is H;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is piperazinyl, R5 is H;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl, R4 is COR8, R8 is cyclohexyl;
X is N, Y is CONR2, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is phenyl;
X is N, Y is NR2CO, R1 is H, CH3, C2H5 or C3H7, R2 is H, R3 is CH2-phenyl.
Preferred compounds are:
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-morpholinobenzamide
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-piperidinobenzamide
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-butoxybenzamide
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-trifluoromethylbenzamide
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-N,N-diethylaminobenzamide
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-trifluoromethylbenzamide
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-(4-piperidon-1-yl)benzamide
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran-3-yl]-4-(hexahydro-1,4-diazepin-5-on-1-yl)benzamide, and
(S)-N-[5-(4-Methylpiperazin-1-yl)-3,4 dihydro-2H-1-benzopyran-3-yl]-4-(4-benzylpiperazin-1-yl)benzamide.
The compounds of the present invention are in the form of the racemate or the (R)- or (S)-enantiomer in the form of a free base or a pharmaceutically acceptable salt or solvate thereof. Compounds in the form of the (S)-enantiomer are preferred ones.
Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric, dibenzoyltartaric, diacetyltartaric, palmoic, ethanedisulfonic, sulfamic, succinic, propionic, glycolic, malic, gluconic, pyruvic, phenylacetic, 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,5-dihydroxybenzoic, 3-hydroxy-2-naphthoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic, naphthalenesulfonic, ascorbic, cyclohexylsulfamic, fumaric, maleic and benzoic acids. These salts are readily prepared by methods known in the art.
The preferred solvates of the compounds of this invention are the hydrates.
Pharmaceutical Formulations
In a second aspect the present invention provides a pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of the compound of formula I as an enantiomer or a racemate in the form of a free base or a pharmaceutically acceptable salt or solvate thereof, optionally in association with diluents, excipients or inert carriers.
According to the present invention the compound of the invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical formulations comprising the active ingredient either as a free base or a pharmaceutically acceptable non-toxic acid addition salt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate and the like in a pharmaceutically acceptable dosage form. The dosage form may be a solid, semisolid or liquid preparation. Usually the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations intended for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.
To produce pharmaceutical formulations containing the compound of the invention in the form of dosage units for oral application, the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or poly-vinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet can be coated with a polymer known to the person skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compound.
For the preparation of soft gelatine capsules, the active substance may be admixed with e.g. a vegetable oil or poly-ethylene glycol. Hard gelatine capsules may contain granules of the active substance using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug can be filled into hard gelatine capsules.
Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in a mixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil. Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.1% to about 20% by weight of the active substance herein described, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharin and carboxymethyl-cellulose as a thickening agent or other excipients known to the person skilled in the art.
Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from about 0.1% to about 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
Suitable daily doses of the compound of the invention in therapeutical treatment of humans are about 0.01-100 mg/kg bodyweight at peroral administration and 0.001-100 mg/kg bodyweight at parenteral administration.
The compound of the invention may be used in a combination with a 5-HT reuptake inhibitor, such as fluoxetine, paroxetine, citalopram, clomipramine, sertraline, alaproclate or fluvoxamin, preferably paroxetine or citalopram. Another possible combination is to use the compound of the invention together with a monoamine oxidase inhibitor, such as moclobemide, tranylcypramine, brofaromide or phenelzine, preferably moclobemide or phenelzine. Still another possible combination is the compound of the invention together with a 5-HT1A antagonist, such as the compounds disclosed in WO 96/33710, preferably (R)-5-carbamoyl-3-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran.
Medical and Pharmaceutical Use
In a further aspect the present invention provides the use of the compounds of formula I in therapy as a h5-HT1B antagonist, partial agonist or full agonist, preferably as an antagonist and the use in the treatment of 5-hydroxytryptamine mediated disorders. Examples of such disorders are disorders in the CNS such as mood disorders (depression, major depressive episodes, dysthymia, seasonal affective disorder, depressive phases of bipolar disorder), anxiety disorders (obsessive compulsive disorder, panic disorder with/without agoraphobia, social phobia, specific phobia, generalized anxiety disorder, posttraumatic stress disorder), personality disorders (disorders of impulse control, trichotellomania), obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders (age associated memory impairment, presenile and senile dementia), pathological aggression, schizophrenia, endocrine disorders (e g hyperprolactinaemia), stroke, dyskinesia, Parkinson""s disease, thermoregulation, pain and hypertension. Other examples of hydroxytryptamine mediated disorders are urinary incontinence, vasospasm and growth control of tumors (e g lung carcinoma).
Methods of Preparation
The present invention also relates to processes for preparing the compound of formula I. Throughout the following description of such processes it is understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d T. W. Greene, Wiley-Interscience, New York, 1991.
Methods of Preparation of Intermediates
1. In the Case Where Y is NR2CO and X is N
(i) Benzylation of the compound of the formula II, described in: Thorberg S-O.; Hall H.; xc3x85kesson C.; Svensson K.; Nilsson J. L. G. Acta Pharm. Suec. 1987, 24(4), 169-182 as a racemate or in the patent application WO 93/07135 as an enantiomer, 
to obtain a compound of formula III may be carried out by reaction with a suitable benzylation agent, e.g. a benzyl halide such as benzyl bromide or benzyl chloride or an activated alcohol, e.g. benzyl mesylate or benzyl tosylate. The reaction may be carried out using a salt or the base of compound II in a suitable solvent, e.g. N,N-dimethylformamide, acetone or acetonitrile, with a suitable base, e.g. NaOH, NaHCO3, K2CO3 or a trialkylamine such as triethylamine, at a temperature within the range of +20xc2x0 C. to +150xc2x0 C. The presence of a suitable catalyst, e.g. potassium iodide or sodium iodide, may increase the speed of the reaction.
(ii) Demethylation of the compound of formula III: 
to obtain a compound of formula IV may be carried out by treating the compound with an acidic reagent such as aqueous HBr, HI, HBr/CH3COOH, BBr3, AlCl3, pyridine-HCl or with a basic nucleophilic reagent such as CH3C6H4Sxe2x88x92 or C2H5Sxe2x88x92 in a suitable solvent. Suitable solvents may be methylene chloride or chloroform and the reaction may occur between xe2x88x9278xc2x0 C. and +60xc2x0 C.
(iii) Conversion of the compound of formula IV to a compound of formula V: 
may be carried out by the reaction with a compound of formula VI: 
where Lg denotes for a leaving group, e.g. a halogen such as chlorine, bromine or iodine or an alkane- or arenesulfonyloxy group such as a p-toluenesulfonyloxy group and Ra and Rb are hydrogen or a lower alkyl group, e.g. methyl. The process may be carried out with a salt of the compound of formula IV obtained by reaction with a base such as K2CO3, Na2CO3, KOH, NaOH, BuLi or NaH. The reaction may be conducted in a suitable solvent e.g. an aprotic solvent such as dioxane, N,N-dimethylformamide, tetrahydrofuran, toluene, benzene or petroleum ether and the reaction may occur between +20xc2x0 C. and +150xc2x0 C.
(iv) Rearrangement of a compound of formula V to a compound of formula VII 
may be carried out in a suitable solvent, e.g. aprotic solvent such as N,N dimethylformamide, dioxane, 1,1,3,3-tetramethylurea, tetrahydrofuran or hexamethylphosphoric triamide, with a suitable base, e.g. K2CO3, KOH, potassium tert-butoxide or NaH, at a temperature within the range of +20xc2x0 C. to +150xc2x0 C. The presence of a cosolvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone or hexamethyl-phosphoric triamide in appropriate concentration in the solvent may increase the speed of the reaction.
(v) Hydrolysis of a compound of formula VII to a compound VIII may be carried out under acidic conditions using acids such as H2SO4, HCl or HBr in a suitable solvent, e.g. H2O, ethanol, methanol or mixtures thereof, and the reaction may occur between +20xc2x0 C. and +100xc2x0 C. or under basic conditions using bases such as NaOH or KOH in a suitable solvent, e.g. H2O, ethanol, methanol or mixtures thereof, and the reaction may occur between +20xc2x0 C. and +100xc2x0 C.
(vi) Conversion of compound of formula VIII to a compound of formula IX: 
may be carried out by
a) reaction with a compound of formula X: 
where R1 is C1-C6 alkyl or C3-C6 cycloalkyl. The process may be carried out in a suitable solvent, e.g. an aprotic/anhydrous solvent such as tetrahydrofuran or N,N-dimethylformamide, in the presence of coupling reagent such as N,Nxe2x80x2-carbonyldiimidazole and the reaction may occur between +20xc2x0 C. and +130xc2x0 C. The reaction is followed by the reduction of the imide with a suitable reducing agent, e.g. LiAlH4, in a suitable solvent, e.g. diethyl ether or tetrahydrofuran at a temperature between +20xc2x0 C. and reflux, or
b) by reaction with a compound of formula XI 
where Lg denotes a leaving group, e.g. a halogen such as chlorine, bromine or iodine or an alkane- or arenesulfonyloxy group such as p-toluenesulfonyloxy group and R1 is hydrogen, C1-C6-alkyl or C3-C6 cycloalkyl. The process may be carried out in a suitable solvent such as ethanol, buthanol, N,N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with a suitable base, e.g. K2CO3, NaHCO3 or KOH, and the reaction may occur between +20xc2x0 C. and +150xc2x0 C.
(vii) Conversion of the compound of formula IX to a compound of formula XII: 
where R1 is C1-C6 alkyl or C3-C6 cycloalkyl may be carried out by
a) hydrogenation using a catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent, e.g. acetic acid or ethanol, and at a reaction temperature between +20xc2x0 C. and +120xc2x0 C., or
b) debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd/C and at a reaction temperature between +20xc2x0 C. and reflux.
(viii) Conversion of a compound of formula IX, where R1 is hydrogen, to a compound of formula XIII:
where RC denotes a suitable protecting group, may be carried out by
a) hydrogenation using a catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent, e.g. acetic acid or ethanol, at a reaction temperature between +20xc2x0 C. and +120xc2x0 C., or
b) debenzylation in a suitable solvent such as methanol in the presence of ammonium-formate and Pd/C at a reaction temperature between +20xc2x0 C. and reflux.
Said reaction is followed by the protection of the piperazine ring in a suitable solvent, e.g. methylene chloride or chloroform, with an appropriate protecting reagent e.g. di-tert-butyl dicarbonate with a suitable base, e.g. triethylamine or K2CO3, and at a temperature between xe2x88x9220xc2x0 C. and +60xc2x0 C., resulting in compound of formula XIII.
2. In the Case Where Y is NR2CO and X is CH
(i) Halogenation of the compound of formula XIV, either as a racemate (described in: Thorberg S-O.; Hall H.; xc3x85kesson C.; Svensson K.; Nilsson J. L. G. Acta Pharm. Suec. 1987, 24(4), 169-182), or as an enantiomer 
to obtain a compound of formula XV may be performed by aromatic electrophilic substitution using a suitable halogenation agent such as Br2, Cl2, I2, ICl, or SO2Cl2. The reaction may be carried out using the salt or the base of the compound XIV in an appropriate solvent, e.g. acetic acid, HCl/ethanol or water, with or without a suitable base, e.g. an alkali metal acetate such as sodium acetate and at a reaction temperature between xe2x88x9220xc2x0 C. and room temperature. 
(ii) Benzylation of the compound of the formula XV, either as a racemate or as an enantiomer, to obtain a compound of the formula XVI may be carried out by reaction with a suitable benzylation agent, e.g. benzyl halide such as benzyl bromide or benzyl chloride. The reaction may be carried out using the salt or the base of compound XV in a suitable solvent, e.g. N,N-dimethylformamide, acetone or acetonitrile, with a suitable base such as triethylamine, NaOH, NaHCO3 or K2CO3 at a temperature within the range of +20xc2x0 C. to +150xc2x0 C. The presence of a suitable catalyst, e.g. an alkali metal halide such as potassium iodide or sodium iodide, may increase the speed of the reaction. 
(iii) The conversion of the compound of the formula XVI to the compound of the formula XVII, where R1 is C1-C6 alkyl or C3-C6 cycloalkyl, may be performed by a metal-halogen exchange, in an appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether using a suitable alkyllithium or metal, e.g. butyllithium, lithium or magnesium turnings, followed by treatment with an appropriate piperidone such as N-methyl-4-piperidone and a subsequent suitable workup. The reaction may be performed at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature. 
(iv) The compound of the formula XVII may be reduced to the compound of the formula XVIII by treatment with a suitable reducing agent such as sodium borohydride and a protonating agent such as CF3COOH, CF3SO3H or HCOOH in an appropriate solvent such as tetrahydrofuran or diethyl ether. The reaction may be performed at reaction temperature between 0xc2x0 C. and reflux. 
(v) Demethylation of the compound of the formula XVIII to obtain a compound of formula XIX may be performed by treating the compound with an acidic reagent such as aqueous HBr, HI, HBr/acetic acid, BBr3, AlCl3, pyridine-HCl or with a basic nucleophilic reagent such as C2H5Sxe2x88x92 or CH3C6H4Sxe2x88x92 in a suitable solvent. Suitable solvents may be methylene chloride or chloroform and the reaction may occur between xe2x88x9278xc2x0 C. and +60xc2x0 C. 
(vi) Conversion of the compound of formula XIX to a compound of formula XX may be carried out with a compound such as trifluoromethanesulfonic anhydride in a suitable solvent such as methylene chloride or carbon tetrachloride in the presence of a base such as 2,4,6-collidine, triethylamine or pyridine at a reaction temperature within the range of xe2x88x9278xc2x0 C. to room temperature. 
(vii) Conversion of the compound of formula XX to a compound of formula XXI may be performed by
a) hydrogenation using a catalyst such as palladium, platinum, rhodium or nickel in a suitable solvent such as acetic acid or ethanol at a reaction temperature between +20xc2x0 C. and +120xc2x0 C., or
b) reaction in a suitable solvent such as methanol in the presence of ammonium formate and Pd/C at a reaction temperature between +20xc2x0 C. and reflux.
3. In the Case Where Y is CONR2 and X is N
(i) Nitration of a compound of formula XXII either as a racemate (described in: Thorberg S-O.; Hall H.; xc3x85kesson C.; Svensson K.; Nilsson J. L. G. Acta Pharm. Suec. 1987, 24(4), 169-182), or as an enantiomer to obtain a compound of formula XXIII: 
where Rd is C1-C6 alkyl, may be carried out by aromatic electrophilic substitution using a suitable nitration reagent such as nitric acid or nitric acid and sulfuric acid in a suitable solvent, e.g. acetic acid, acetic anhydride or water, at a reaction temperature between xe2x88x9220xc2x0 C. and room temperature.
(ii) Demethylation of the compound of the formula XXIII to obtain a compound of formula XXIV: 
may be carried out by treating the compound with an acidic reagent such as aqueous HBr, HI, HBr/CH3COOH, BBr3, AlCl3, pyridine-HCl or with a basic nucleophilic reagent such as CH3C6H4Sxe2x88x92 or C2H5Sxe2x88x92. Suitable solvents may be methylene chloride or chloroform and the reaction may occur between xe2x88x9278xc2x0 C. and +60xc2x0 C.
During the demethylation of XXIII, hydrolysis of the ester may occur and the acid function could then be converted back to the ester by methods known by a person skilled in the art (See T. W. Greene, Wiley-Interscience, New York, 1991).
(iii) Conversion of the compound of formula XXIV to a compound of formula XXV: 
may be carried out by the reaction with an activated trifluoromethanesulfonic reagent e.g. trifluoromethanesulfonic anhydride in a suitable solvent such as methylene chloride, chloroform or carbon tetrachloride in the presence of a suitable base such as triethylamine, pyridine or 2,4,6-collidine at a reaction temperature between xe2x88x9278xc2x0 C. and room temperature.
(iv) Conversion of the compound of formula XXV to a compound of formula XXVI may be carried out by: 
a) hydrogenation using a catalyst containing palladium, platinum or nickel in a suitable solvent such as ethanol, methanol or acetic acid and at a reaction temperature between +20xc2x0 C. and +120xc2x0 C. or
b) reaction in a suitable solvent such as methanol in the presence of a ammonium formate such as triethyl ammonium formate and Pd/C and at a reaction temperature between +20xc2x0 C. and reflux.
(v) Conversion of the compound of formula XXVI to a compound of formula XXVII: 
may be carried out by reaction of compound XI: 
where Lg denotes a leaving group, e.g. a halogen such as chlorine, bromine or iodine, or an alkane- or arenesulfonyloxy group such as p-toluenesulfonyloxy group and R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl. The process may be carried out in a suitable solvent such as ethanol, buthanol, N,N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with a suitable base, e.g. K2CO3, NaHCO3 or KOH, and the reaction may occur between +20xc2x0 C. and +150xc2x0 C. During the cyclization reaction of XXVI, hydrolysis of the ester may occur. 
(vi) Hydrolysis of a compound of formula XXVII may be carried out under acidic conditions using acids such as H2SO4, HCl, HBr, in a suitable solvent such as H2O, ethanol, methanol, acetic acid or mixtures thereof at a temperature between +20xc2x0 C. and reflux or under basic conditions using bases such as NaOH or KOH in a suitable solvent such as as H2O, ethanol, methanol or mixtures thereof at a temperature between +20xc2x0 C. and reflux, resulting in a compound of formula XXVIII, where R1 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl.
(vii) When R1 is hydrogen, protection of a compound of formula XXVIII as a compound of formula XXIX where RC is a protecting group: 
may be carried out by the reaction with a suitable protecting reagent such as di-tert-butyl dicarbonate in a suitable solvent, e.g methylene chloride or chloroform, with a suitable base such as triethylamine or K2CO3 and at a temperature between xe2x88x9220xc2x0 C. and +60xc2x0 C.
4.
(i) Conversion of a compound of formula XXX to a compound of formula XXXI: 
may be carried out by
a) hydrolysis of the nitrile in compound of formula XXX in a suitable solvent such as aqueous methanol or aqueous ethanol in the presence of a suitable base such as NaOH or KOH at a reaction temperature between room temperature and reflux, followed by
b) hydrolysis of the above formed amide and the ketal under acidic conditions in a suitable solvent such as aqueous methanol, aqueous ethanol or water in the presence of a suitable acid such as HCl or HBr at a reaction temperature between room temperature and reflux.
(ii) Conversion of a compound of formula XXXI to a compound of formula XXXII: 
may be carried out by reaction with a suitable azide such as sodium azide in a suitable acid or mixtures of acids such as H2SO4 and acetic acid at a reaction temperature between 0xc2x0 C. and +50xc2x0 C.
(iii) Conversion of a compound of formula XXXIII to a compound of formula XXXIV: 
may be carried out by reaction with 1-benzylpiperazine in a suitable solvent such as N,N-dimethylformamide, dimethylsulfoxide or acetonitrile in the presence of a suitable base such as KOH or K2CO3 at a reaction temperature between +50xc2x0 C. and +150xc2x0 C. 
(iv) Hydrolysis of a compound of formula XXXIV to a compound XXXV may be carried out under acidic conditions using acids such as H2SO4, HCl or HBr in a suitable solvent, e.g. H2O, ethanol, methanol or mixtures thereof, and the reaction may occur between +20xc2x0 C. and +100xc2x0 C. or under basic conditions using bases such as NaOH or KOH in a suitable solvent, e.g. H2O, ethanol, methanol or mixtures thereof, and the reaction may occur between +20xc2x0 C. and +100xc2x0 C. 
(v) Halogenation of a compound of formula XXXVI to a compound of formula XXXVII where Hal denotes bromine, chlorine or iodine may be performed by a reagent such as ICl or Br2, Cl2 or SO2Cl2 with a suitable base such as sodium acetate in a suitable solvent such as acetic acid at a reaction temperature between +20xc2x0 C. and +50xc2x0 C.
(vi) Conversion of a compound of formula XXXVII to a compound of formula XXXVIII: 
may be carried out by a metal-halogen exchange, in an appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether using a suitable alkyl-lithium or metal, e.g. butyllithium, lithium or magnesium turnings, followed by treatment with carbon dioxide at a reaction temperature between xe2x88x9278xc2x0 C. and room temperature.
Methods of Preparation of End Products
Another object of the invention is a process A(i), A(ii), A(iii), B(i), B(ii) or C for the preparation of the compound of general formula I by
A(i)
acylation, in the case when R1 is C1-C6 alkyl or C3-C6 cycloalkyl, Y is NR2CO, R2 is hydrogen and X and R3 are as defined in general formula I above, of a compound of formula A, 
with an activated carboxylic acid R3xe2x80x94COLg1 where Lg1 is a leaving group or by using a carboxylic acid R3xe2x80x94COOH with an activating reagent.
Thus, the acylation according to the process A(i) may be carried out with an appropriate activated carboxylic acid, R3COLg1 where R3 is as defined above and Lg1 is a leaving group, such as halogen, e.g. chlorine, in a suitable solvent such as methylene chloride or chloroform with a suitable base, e.g. a trialkylamine such as triethylamine, at a temperature between xe2x88x9220xc2x0 C. and reflux temperature or by using an carboxylic acid, R3COOH wherein R3 is as defined above with an activating reagent, e.g. N,Nxe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-dicyclohexylcarbodiimide or diphenylphosphinic chloride, with a suitable base such as N-methylmorpholine in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran and the reaction may be conducted at a temperature between +20xc2x0 C. and +150xc2x0 C.
A(ii)
acylation, in the case when R1 is hydrogen, Y is NR2CO, R2 is hydrogen, Rc is a protecting group and X and R3 are as defined in general formula I above, of a compound of formula B 
with an activated carboxylic acid R3xe2x80x94COLg1 where Lg1 is a leaving group or by using a carboxylic acid R3xe2x80x94COOH with an activating reagent, followed by the removal of the protecting group Rc;
Thus, the acylation according to the process A(ii) may be carried out with an appropriate activated carboxylic acid, R3COLg1 where R3 is as defined above and Lg1 is a leaving group, such as halogen, e.g. chlorine, in a suitable solvent such as methylene chloride or chloroform with a suitable base, e.g. a trialkylamine such as triethylamine, or by using a carboxylic acid, R3COOH where R3 is defined as above, with an activating reagent, e.g. N,Nxe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-dicyclohexylcarbodiimide or diphenylphosphinic chloride, with a suitable base such as N-methylmorpholine in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran and the reaction may be conducted at a temperature between +20xc2x0 C. and +150xc2x0 C., followed by removal of the protecting group Rc by hydrolysis in a suitable solvent such as methylene chloride or chloroform with a suitable acid such as trifluoroacetic acid at a temperature between +20xc2x0 C. and +60xc2x0 C.
A(iii)
debenzylation, in the case when R1 is C1-C6 alkyl or C3-C6 cycloalkyl, X and R2 is as defined in general formula I above and R9 below is C1-C6 alkyl, C3-C6 cycloalkyl, (CH2)mOH wherein m is 2-6 or COR8, of a compound of formula Ia, followed by a) hydrogenation, b) alkylation, c) alkylation and removal of a protecting group or d) acylation: 
Thus, in the case when R9 is H the hydrogenation a) above of a compound of formula Ia may be carried out by using a catalyst such as palladium, platinum, rhodium or nickel in a suitable solvent such as acetic acid or ethanol at a reaction temperature between +20xc2x0 C. and +120xc2x0 C., or reaction in a suitable solvent such as methanol in the presence of ammonium formate and Pd/C at a reaction temperature between +20xc2x0 C. and reflux.
In the case when R9 is C1-C6 alkyl or C3-C6 cycloalkyl the debenzylation is followed by the alkylation b) above using a suitable alkylation reagent such as R1-Lg where Lg is a suitable leaving group, e.g. a halogen such as chlorine, bromine or iodine, or an alkane- or arenesulfonyloxy group such as a p-toluenesulfonyloxy group and R1 is C1-C6 alkyl. The reaction may be carried out in a suitable solvent such as N,N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran with a suitable base such as K2CO3, NaHCO3, NaOH or a trialkylamine such as triethylamine. The reaction may be conducted at a temperature between +20xc2x0 C. and +120xc2x0 C. or, reductive alkylation with a compound R1xe2x80x94CHO, where R1 is hydrogen or C1-C5 alkyl, or with a C3-C6 cyclic ketone, in the presence of a reductive agent such as sodium cyanoborohydride, sodium borohydride or catalytically with H2 and a suitable catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent, e.g. tetrahydrofuran, dioxane, methanol or ethanol. A proton donor such as p-toluenesulfonic acid can be used to catalyze the formation of the imine/enamine and adjustment of pH to slightly acidic by an appropriate acid such as acetic acid may speed up the reaction.
In the case when R9 is (CH2)mOH and m is 2-6, the debenzylation is followed by the alkylation c) above by using a suitable alkylation reagent such as BnO(CH2)mLg where Lg is a suitable leaving group, e.g. a halogen such as chlorine, bromine or iodine, or an alkane- or arenesulfonyloxy group such as a p-toluenesulfonyloxy group and R1 is C1-C6 alkyl. The reaction may be carried out in a suitable solvent such as N,N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran with a suitable base such as K2CO3, NaHCO3, NaOH or a trialkylamine such as triethylamine and may be conducted at a temperature between +20xc2x0 C. and +120xc2x0 C. The reaction is followed by removal of a protecting group, such as a benzyl group, by hydrogenation using a catalyst such as palladium, platinum, rhodium or nickel in a suitable solvent such as acetic acid or ethanol at a reaction temperature between +20xc2x0 C. and +120xc2x0 C., or reaction in a suitable solvent such as methanol in the presence of ammonium formate and Pd/C at a reaction temperature between +20xc2x0 C. and reflux.
In the case when R9 is COR8 the debenzylation is followed by the acylation d) above by using an appropriate activated carboxylic acid, R8COLg1 where R8 is as defined above and Lg1 is a leaving group, such as halogen, e.g. chlorine, in a suitable solvent such as methylene chloride, chloroform or N,N-dimethylformamide with a suitable base, e.g. a trialkylamine such as triethylamine or by using a carboxylic acid, R6COOH where R6 is defined as above, with an activating reagent, e.g. N,Nxe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-dicyclohexylcarbodiimide or diphenylphosphinic chloride, with a suitable base such as N-methylmorpholine in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran and the reaction may be conducted at a temperature between +20xc2x0 C. and +150xc2x0 C.
B(i)
reacting, in the case when R1 is C1-C6 alkyl or C3-C6 cycloalkyl, Y is CONR2, X, R2 and R3 are as defined in general formula I above, an activated carboxylic acid of a compound of formula C: 
with an aniline or amine HNR2R3.
Thus, conversion according to the process B(i) of a compound of formula C may be carried out by activation of the acid function of a compound as an acid halide such as an acid chloride or by using an activating reagent such as N,Nxe2x80x2-carbonyldiimidazole or N,N-dicyclohexylcarbodiimide in a suitable solvent, e.g. methylene chloride, chloroform, toluene, N,N-dimethylformamide, dioxane or tetrahydrofuran, followed by the addition of an appropriate amine or aniline HNR2R3 and the reaction may occur between 0xc2x0 C. and +120xc2x0 C.
B(ii)
reacting, in the case when R1 is hydrogen, Y is NR2CO, Rc is a protecting group and X, R2 and R3 are as defined in general formula I above, an activated carboxylic acid of a compound of formula D: 
with an aniline or amine HNR2R3, followed by removal of the protecting group Rc.
Thus, conversion according to the process B(ii), of a compound of formula D, may be carried out by activation of the acid function of a compound as an acid halide such as an acid chloride or by using an activating reagent such as N,Nxe2x80x2-carbonyldiimidazole or N,N-dicyclohexylcarbodiimide in a suitable solvent, e.g. methylene chloride, chloroform, toluene, N,N-dimethylformamide, dioxane or tetrahydrofuran, followed by the addition of an appropriate amine or aniline HNR2R3 and the reaction may occur between 0xc2x0 C. and +120xc2x0 C., followed by removal of the protecting group RC by methods known by a person skilled in the art such as hydrolysis in a suitable solvent such as methylene chloride or chloroform with a suitable acid, e.g. trifluoroacetic acid, at a temperature between +20xc2x0 C. and +60xc2x0 C.
C
reaction, in the case when R1 is C1-C6 alkyl or C3-C6 cycloalkyl, Y is NR2CONR2, R2 is hydrogen and X and R3 are as defined in general formula I above, a compound of formula A: 
with a suitable azide in the presence of carboxylic acid, R3COOH.
Thus, reaction according to the process C may be carried out with an appropriate azide such as diphenylphosphoryl azide in the presence of a carboxylic acid, R3COOH where R3 is as defined above in a suitable solvent such as acetonitrile and the reaction may be conducted at a temperature between +20xc2x0 C. and reflux temperature.
Intermediates
Another object of the invention is a compound having the formula: 
wherein
X=N or CH;
Z=NH2 or COOH;
R1 is H, C1-C6 alkyl or C3-C6 cycloalkyl.
The invention is illustrated but not restricted to the following working examples.